Erlinda M. Gordon, Neal S. Chawla, Sant P. Chawla and Frederick L. Hall
The Sarcoma Oncology Center, Santa Monica CA 90405 and Counterpoint Biomedica LLC, Santa Monica CA 90405
Recent developments in the fields of cancer gene therapy and immunotherapy are exceedingly encouraging. These innovations are the fruits of basic research in molecular and cellular biology, biochemistry, and immunology. Among USFDA-approved therapies are dendritic cell therapy for prostate cancer, oncolytic viruses and immune checkpoint inhibitors for metastatic unresectable melanoma and non-small cell lung cancer. In earlier phase development are targeted lentivectors expressing the NY-ESO1 gene (LV305) and targeted retrovectors expressing a cytocidal dominant negative cyclin G1 gene (Rexin-G) or a cytokine gene, GM-CSF (Reximmune-C). Two U.S.-based clinical trials showed that the use of Rexin-G as monotherapy for advanced metastatic disease was associated with improved dose-dependent over-all survival with minimal systemic toxicity in chemotherapy-resistant advanced sarcoma and gemcitabine-failed pancreatic cancer. Long term follow-up of survivors showed that one patient with gemcitabine/5 fluorouracil-failed metastatic pancreatic cancer, and two patients with chemotherapy-resistant metastatic sarcoma are still alive with no evidence of active disease 7 years after the start of Rexin-G therapy, and 6 years after discontinuation of Rexin-G and all cancer therapies. Further, a recent phase 1 clinical trial for chemotherapy-resistant solid malignancies (The Genevieve Protocol) evaluated the use of an optimal dose of Rexin-G and escalating doses of Reximmune-C. This dual targeted approach aimed at both tumor eradication and in situ cancer vaccination. Rexin-G was given first, to kill the cancer cells and expose tumor antigens, followed by Reximmune-C administration to recruit the host immune cells to the tumor site, thus inducing an in situ autoimmunization. This first-in-human targeted gene therapy regimen showed a one-year survival duration of 86% with no reported serious adverse events. The progressive shift in cancer drug development towards targeted genetic medicine and cancer immunotherapy raises hope for improved outcomes for many types of cancer in the future.